In general, it is known that cyclic guanosine monophosphate (“cGMP”), which is an intracellular secondary messenger, is decomposed and inactivated by cyclic nucleotide phosphodiesterases (“PDEs”) that hydrolyze cGMP into 5′-GMP. Such phosphodiesterases are widely distributed in many cell types and tissues of the living body. When PDE activity is inactivated by a an inhibitor of a cGMP-degrading phosphodiesterase, the level of cGMP in cells is increased, in turn triggering several physiological responses, including relaxation of vascular smooth muscle, relaxation of bronchial smooth muscle, and inhibition of platelet aggregation.
Moreover, it has been reported that certain cGMP-specific PDE inhibitors (i.e., inhibitors of phosphodiesterase Type V, or “PDE V inhibitors”) are useful in the treatment of diseases caused by a functional disorder of cGMP signaling, including hypertension, angina pectoris, myocardial infarction, chronic or acute heart failure, pulmonary hypertension, etc. (see, e.g., International Patent Publication No. WO 96/05176), and prostatic hyperplasia (see Australian Patent Publication No. 9955977). It has also been reported that PDE V inhibitors can be useful in the treatment of female sexual dysfunction (see, e.g., U.S. Pat. No. 6,469,016 to Place et al., of common assignment herewith to Vivus, Inc.; and Vemulapalli et al. (2000) Life Sciences 67: 23-29), diabetic gastroparesis (Watkins et al. (2000) J. Clin. Invest. 106: 373-384), achalasia (Bortolotti et al. (2000) Gastroenterology 118: 253-257), diarrhea (Mule et al. (1999) Br. J. Pharmacol. 127: 514-520), constipation (Bakre et al. (2000)J. Cell. Biochem. 77: 159-167) and asthma (Turner et al. (1994) Br. J. Pharmacol. 111: 1198-1204).
Furthermore, sildenafil, 1-[4-ethoxy-3-(6,7-dihydro-1-methyl-7-oxo-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5-yl)-phenylsulfonyl]-4-methylpiperazine citrate, a cGMP-specific PDE V inhibitor, is now widely prescribed for the treatment of penile erectile dysfunction (as Viagra®, Pfizer), as are the cGMP-specific PDE V inhibitors tadalafil (as Cialis®, Lilly ICOS), and vardenafil (as Levitra®, Bayer AG). However, these PDE V inhibitors have been reported to have side effects such as headache, facial suffusion, gut disorder, rhinitis, color sense disorder, penile erectile continuance, back pain, abdominal pain, and nausea (see, e.g., Irwin et al. (1998) The New England Journal of Medicine 338(20):1397-1404; Morales et al. (1998) International Journal of Impotence Research 10(2): 69-73; and Goldenberg (1998) Clinical Therapeutics 20(6): 1033-1048). It has also been reported that the side effects of sildenafil affect vision, including blurriness and loss of peripheral vision.
In U.S. Pat. No. 6,656,935 to Yamada et al. (Tanabe Seiyaku Co. Ltd., Osaka, JP), the synthesis of a new class of cGMP-specific PDE inhibitors is described. These compounds are N-heterocyclic-substituted compounds having the general structure (I)

wherein: Ring A is a substituted or unsubstituted nitrogen-containing heterocyclic group; R1 is a substituted or unsubstituted lower alkyl group, a substituent having the formula —NH-Q-R3 wherein Q is a lower alkylene group or a single bond and R3 is a substituted or unsubstituted nitrogen-containing heterocyclic group, or a substituent having the formula —NH—R4 wherein R4 is substituted or unsubstituted cycloalkyl; R2 is substituted or unsubstituted aryl; and one of Y and Z is ═CH— and the other is ═N—, and also include pharmaceutically acceptable salts of the compounds. These compounds, particularly 4-[(3-chloro-4-methoxybenzyl)amino]-2-[2-(hydroxymethyl)-1-pyrrolidinyl]-N-(2-pyrimidinylmethyl)-5-pyrimidinecarboxamide, or “avanafil,” having the structure
are particularly useful in the prophylaxis or treatment of erectile dysfunction with few side effects.
Administration of these therapeutic agents for the treatment of erectile dysfunction is generally on an as-needed basis rather than as part of an ongoing dosage regimen. It is also desirable that any erectile dysfunction pharmacotherapy be fast acting, so that a minimum of scheduling or advance planning is required prior to sexual activity. Although “immediate release” or “rapid release” dosage forms, including orally disintegrating tablets, have been known in the art for some time, various factors can significantly reduce the absorption of drugs from such tablets. For instance, certain drugs such as avanafil and its analogs are soluble in aqueous media at a low pH, but at elevated pH, such as that of the duodenum, the drug can precipitate quickly upon leaving the stomach and entering the duodenum, significantly reducing the likelihood of rapid absorption. If one could maintain a low enough local pH for the drug to remain in a dissolved state, absorption would not be a problem; there is difficulty, however, in maintaining a local low pH in the duodenum.